URSODEOXYCHOLIC ACID

Ursodeoxycholic acid is also known as Ursodiol  and the abbreviation UDCA, is one of the secondary bile acids, which are metabolic byproducts of intestinal bacteria.

3α,7β-dihydroxy-5β-cholan-24-oic acid

OR

(R)-4-((3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-

10,13-dimethylhexadecahydro-

1H-cyclopenta[a]phenanthren-17-yl)pentanoic acid

Formula  -  C24H40O4

Mol. mass  -  392.56 g/mol

Endogenous effects

Primary bile acids are produced by the liver and stored in the gall bladder. When secreted into the intestine, primary bile acids can be metabolized into secondary bile acids by intestinal bacteria. Primary and secondary bile acids help the body digest fats. Ursodeoxycholic acid helps regulate cholesterol by reducing the rate at which the intestine absorbs cholesterol molecules while breaking up micelles containing cholesterol. Because of this property, ursodeoxycholic acid is used to treat (cholesterol) gallstones non-surgically.

While some bile acids are known to be colon tumor promoters (e.g. deoxycholic acid), others such as ursodeoxycholic acid are thought to be chemopreventive, perhaps by inducing cellular differentiation and/or cellular senescence in colon epithelial cells.

It is believed to inhibit apoptosis.

Ursodeoxycholic acid has also been shown experimentally to suppress immune response such as immune cell phagocytosis. Prolonged exposure and/or increased quantities of systemic (throughout the body, not just in the digestive system) ursodeoxycholic acid can be toxic.

Pharmaceutical USE

Ursodeoxycholic acid is marketed under the trade names Actigall, Ursosan, Ursofalk, BILIVER, Egyurso, Urso, Urso Forte, Deursil and Coric.

Ursodeoxycholic acid can be chemically synthesized and was brought to market by the Montreal-based Axcan Pharma in 1998, which continues to market the drug.

The drug reduces cholesterol absorption and is used to dissolve (cholesterol) gallstones in patients who want an alternative to surgery. The drug is very expensive, however, and if the patient stops taking it, the gallstones tend to recur if the condition that gave rise to their formation does not change. For these reasons, it has not supplanted surgical treatment by cholecystectomy.

It is the only FDA approved drug to treat primary biliary cirrhosis.

A Cochrane review to evaluate if ursodeoxycholic acid has any beneficial effect in primary biliary cirrhosis patients included 16 randomized clinical trials with a total of 1447 patients. The primary outcome measures were mortality and mortality or liver transplantation. Although treatment with ursodeoxycholic acid showed a reduction in liver biochemistry, jaundice, and ascites, it did not decrease mortality or liver transplantation.

In absence of biochemical response to 13-15mg/kg/day ursodeoxycholic acid, its use is associated with an incidence of 20% hepatocellular carcinoma in patients with primary biliary cirrhosis in 15 years.

In children, its use is not licensed, as its safety and effectiveness are not established.

In double the recommended daily dose ursodeoxycholic acid reduces elevated liver enzyme levels in patients with primary sclerosing cholangitis, but its use was associated with an increased risk of serious adverse events (the development of cirrhosis, varices, death or liver transplantation) in patients who received ursodeoxycholic acid compared with those who received placebo). After adjustment for baseline stratification characteristics, the risk was 2.1 times greater for death,transplantation, or minimal listing criteria in patients on ursodeoxycholic acid than for those on placebo (P = 0.038). Serious adverse events, were more common in the ursodeoxycholic acid group than the placebo group

Research by the Imperial College London has produced promising results in the treatment of arrhythmia, both in patients who have suffered a heart attack and in foetuses, by using ursodiol to change the electrical properties of myofibroblast cells. Myofibroblasts disrupt the transmission of electrical signals controlling heart rhythm.

SOURCE

The drug is generally not derived from animals.However, it is believed up to 10,000 bile bears are kept on farms in China, Vietnam and South Korea for the purpose of harvesting ursodeoxycholic acid. Ursodeoxycholic acid is found in large quantities in bear bile.

Indication & Dosage

Dissolution of cholesterol-rich gallstones

Adult: 6-12 mg/kg daily as a single dose at bedtime or in 2-3 divided doses continued for 3-4 mth after radiological disappearance of stones. Doses may be divided unequally with a higher dose given before bedtime to counteract increase in biliary cholesterol saturation which occurs in early morning. Max: 15 mg/kg.

Hepatic impairment:Chronic liver disease (except primary biliary cirrhosis): use with caution.

Primary biliary cirrhosis

Adult: 10-15 mg/kg daily in 2-4 divided doses.

Prophylaxis of gallstones in patients undergoing rapid weight loss

Adult: 300 mg bid.

Hepatic impairment: Chronic liver disease (except primary biliary cirrhosis): use with caution.

DRUG INTERACTIONS

Cholestyramine, charcoal and antacids may reduce effectiveness. Aluminum-based antacids may reduce absorption. Oestrogens and clofibrate may counteract effectiveness of ursodeoxycholic acid by increasing cholesterol elimination in bile. Possible increase in ciclosporin serum concentration. Decreased effectiveness of dapsone. Possible decrease in serum ciprofloxacin and nitrendipine.

Mechanism of Action     

Ursodeoxycholic acid suppresses hepatic synthesis and secretion of cholesterol and also inhibits intestinal absorption of cholesterol.

Absorption: Rapidly and completely absorbed from the GI tract.

Distribution:Protein binding: 96-98%. Undergoes enterohepatic recycling.

Metabolism:Partly conjugated in the liver before being excreted into the bile. Free and conjugated forms undergo 7a-dehydroxylation to lithocholic acid under the influence of gut bactera. Some are reabsorbed and then further conjugated and sulfated by the liver.

Excretion:Faeces.

Brand Names

Acido Ursodesossicolico Actavis

Actavis Italy, Italy

Acido Ursodesossicolico Angenerico

Angenerico, Italy

Acido Ursodesossicolico Doc

DOC Generici, Italy

Acido Ursodesossicolico Dorom

Dorom, Italy

Acido Ursodesossicolico EG

EG, Italy

Acido Ursodesossicolico Mylan

Mylan, Italy

Acido Ursodesossicolico ratiopharm

ratiopharm Italia, Italy

Acido Ursodesossicolico Winthrop

Winthrop Ph.Italia, Italy

Actigall

Novartis, New Zealand; Watson, United States

Adursal

Leiras, Finland

Audecol

Ariston, Argentina

Bilenor (Ursodeoxycholic Acid and Chenodeoxycholic Acid)

Myung Moon, South Korea

Bilifalk

Dr Falk, Spain

Buraue

Yoshindo, Japan

Canlin

Everest, Taiwan

Choleron

Aversi, Georgia

Cholit-Ursan

STADA, Germany

Choludexan

Sigma, Georgia

Cisbile

Winston, Taiwan

Clotipide

AC Farma, Peru

Coleretik

Sherfarma, Peru

Daewoongursa

Daewoong, Vietnam

Delursan

Axcan, France

Desoxil

Crinos, Italy

Destolit

Norgine, United Kingdom; Sanofi-Aventis, Portugal

Deursil

Sanofi-Aventis, Italy

De-ursil

Sanofi-Aventis, Switzerland

De-ursil RR

Sanofi-Aventis, Switzerland

De-ursil RR mite

Sanofi-Aventis, Switzerland

Dexo

Dominguez, Argentina

Estazor

Fahrenheit, Indonesia

Fraurs

Francia Farmaceutici, Italy

Genurso

Genovate, Taiwan

Legan

Chin Teng, Taiwan

Liconor

Opsonin, Bangladesh

Ligat

TTY Biopharm, Taiwan

Lipo

Gentle, Taiwan

Lithofalk (Ursodeoxycholic Acid and Chenodeoxycholic Acid)

Falk, Germany

Litoff

Caber, Italy

Litomen

Best, Colombia

Litursol

Crinos, Italy

PMS-Ursodiol C

Pharmascience, Canada

Precoat

Tatsumi Kagaku, Japan

Proursan

Pro.Med., Poland

Reptor

Fuso Pharmaceutical, Japan

Sodan

Chen Ho, Taiwan

Solutrat

Sandoz, Argentina

Tantosan

Newai Chem, Taiwan

Ubiron

Medisa Shinyaku, Japan

UDC AL

Aliud, Germany

UDC HEXAL

Hexal, Germany

UDCA Ferring

Ferring, Argentina

Udihep

Win-Medicare, India; Win-Medicare, Thailand

Udihep Forte

Win-Medicare, India

Udoxyl

Ind-Swift, India

Uliden

Swiss Pharm, Taiwan

Urchil

Aamorb, India

Urchil Forte

Aamorb, India

Urdafalk

Darya-Varia, Indonesia; Falk, Indonesia

Urdahex

Kalbe, Indonesia

Urdenacin

Taiyo Pharmaceutical, Japan

Urdes

Errekappa Euroterapici, Italy

Urdeston

Towa Yakuhin, Japan

Urdex

Towa Yakuhin, Japan

Urdox

CP, Malta; Wockhardt, United Kingdom

Urose

Hwang's, Taiwan

Uroso

Johnson, Taiwan

Urosofalk

Dr. Falk, Portugal

Ursa 200MG

Daewoong, Vietnam

Ursa

Dae Woong, South Korea; Daewoong, Thailand

Ursacol

Zambon, Brazil; Zambon, Colombia; Zambon Italia, Italy

Ursidesox

Duncan, Argentina

Ursilon

IBI, Italy

Urso Forte

Aptalis, United States

Urso Heumann

Heumann, Germany

Urso

Aptalis, United States; Axcan, Canada; Mitsubishi Tanabe Pharma, Hong Kong; Mitsubishi-Tokyo, Taiwan; Tanabe Mitsubishi Pharma, Japan

Urso DS

Axcan, Canada

Ursobil

ABC Farmaceutici, Georgia; ABC Farmaceutici, Italy

Ursobilane

Estedi, Spain

Ursocam

Polfarmex, Poland

Ursocel

ABL Pharma, Peru

Ursochol

Zambon, Belgium; Zambon, Switzerland; Zambon, Germany; Zambon, Spain; Zambon, Indonesia; Zambon, Netherlands

Ursocid

Ta Fong, Taiwan

Ursodeoxycholic acid Zensei

Zensei Yakuhin, Japan

Ursodeoxycholic Acid-Daewoong Pharm

Daewoong Pharmaceutial Co. Ltd, China

Ursodeoxycholic Acid-Sunve Pharm

Sunve, China

Ursodeoxycholzuur Imphos

Imphos, Netherlands

Ursodesoxycholic Acid

Ying Yuan, Taiwan

Ursodil

General Pharma, Bangladesh

Ursodiol CorePharma

CorePharma, United States

Ursodiol Epic Pharma

Epic Pharma, United States

Ursodiol Glenmark

Glenmark, United States

Ursodiol Lannett

Lannett, United States

Ursodiol Mylan

Mylan, United States

Ursodiol RR Zentiva

Sanofi-Aventis, Switzerland

Ursodiol Teva

Teva, United States

Ursodiol Watson

Watson, United States

Ursodiol Zentiva

Sanofi-Aventis, Switzerland

Ursodiol

HLB, Argentina

Ursodox

Signova, India

Ursofalk

Farmasa, Mexico; ARIS, Turkey; Biotoscana, Chile; Biotoscana, Colombia; Biotoscana, Peru; Cevallos, Argentina; Codali, Belgium; Codali, Luxembourg; Dr Falk, Hong Kong; Dr. Falk, Israel; Dr. Falk, Norway; Dr. Falk, Russian Federation; Dr. Falk Pharma, Czech Republic; Dr. Falk Pharma, Serbia; Eureco, Netherlands; Falk, Bosnia & Herzegowina; Falk, China; Falk, Germany; Falk, United Kingdom; Falk, Hungary; Falk, Ireland; Falk, Lithuania; Falk, Malta; Falk, Philippines; Falk, Poland; Falk, Romania; Falk, Singapore; Falk, Slovakia; Falk, Thailand; Falk Pharma GmbH, Latvia; Farmak, Estonia; Galenica, Greece; IFET, Greece; Meda, Sweden; Merck, Austria; Orphan, Australia; Salus, Slovenia; Schwabe, Costa Rica; Schwabe, Guatemala; Schwabe, Honduras; Schwabe, Panama; Schwabe, El Salvador; Tramedico, Netherlands; Vifor, Switzerland; Würth, Croatia (Hrvatska); Zydus Cadila, India

Ursoflor

So.Se. Pharm, Italy

Ursogal

Galen, United Kingdom

Ursol

Siu Guan, Taiwan

Ursolic

Gentle, Taiwan; Guardian Pharmatama, Indonesia

Ursolin

Berlin, Thailand

Ursolisin

Magis, Italy

Ursolit

CTS, Israel

Ursolvan

Sanofi-Aventis, France

Ursomac

GMP, Georgia

Ursomax

Altius, Argentina

Ursophalc

Falk, Georgia

Ursopol

ICN, Poland

Ursosan

Evolan, Sweden; Pro.Med.CS, Bosnia & Herzegowina; Pro.Med.CS, Czech Republic; Pro.Med.CS, Estonia; Pro.Med.CS, Georgia; Pro.Med.CS, Lithuania; Pro.Med.CS, Romania; Pro.Med.CS, Serbia; Pro.Med.CS, Slovenia; Pro.Med.CS, Slovakia

Ursotan

Sanofi-Aventis, South Africa

Ursultec

Otifarma, Italy

Urzac

Quesada, Argentina

Usol

Shyh Dar, Taiwan